New tropeine derivatives



United States Patent NEW TROPEINE DERIVATIVES Kai-01y Nador and Laszlo Gyerrnek, Budapest, Hungary,

assignors to Licencia Talalnianyokat Ertekesito I Vallalat, Budapest, Hungary N0 Drawing. Application August 6, 1956 Serial No..602,461

7 Claims. (Cl. 260-'292) This invention is concerned with certain novel tropeine derivatives, more particularly 4-diphenyl-methyl-tropeiltropinium-halide.

It is an object of this invention to provide a process for established that the quaternary tropeines possess gan- "ice Of these compounds we have produced those, wherein R R and R signify the following substituents:

. All these quaternary tropane derivatives possess a ganglionic blocking eifect, which, selectively blocks the autonomic ganglia.

Attempts have been -made to produce compounds, which not only paralyze the autonomic ganglia, but also possess a parasympatholytic efiect thus combining these glionic blocking effect, the term tropeines being understood to mean esters of tropine (trans-tropanol) and of 1p-tropine (cis-tropanol). The general formula of these compounds is CHO.R

two efiects in an optimal manner. However, compounds Patented May 6, 8

of this kind are not known, and thus part of the known compounds are predominantly ganglionic blocking in their effect, as e. g. tetraethylammonium-bromide, 1,6-

heXamethylene-bis-trimethyl-ammonium-bromide, or the tropane derivatives enumerated above under 1 -10 whilst in another 'part of the known compounds the parasympatholytic efiect is predominant. Such compounds are e. g. atropine, ,B-diethyl-aminoethyl-xanthene-9-carboxylic acid ester-bromomethylate.

It now has surprisingly been found during thecourse of our investigations, that tropic acid esters of the 4- j.diphenyl-methyl-tropinium-halides difier from the tropine derivatives enumerated above under 1-10, and possess not only a ganglionic blocking effect but also, a marked parasympatholytic effect. Owing to these special proper-' 'ties our new compounds form the first member of a hitherto unknown series of medicaments. We propose to i designate the combined ganglionic blocking effect and' t t parasympatholytic efiect by the expression gangliocholy- 0 lythic.

The invention therefore provides as new compounds,

where X is halogen, R an acyl-residue or hydrogen, R compounds of the general formula hydrogen or an alkyl-, aryl-, an arylor aralkyl-group, if desired, substituted in the nucleus. 7 e

Queen-on,

aC-N CH2OH CHr CHz----CH-C 2 '7 6Q course of the reaction is as follows:

clId-cO-TIQ Alternatively dl-tropic acid ester of the tropine may of hydrogen bromide gas (approx. Shours) takes place. be first'reacted Wlth a d n y q y halide to yield For the purpose of splitting of the acetyl-residue the a {P y y p the Q -E Q P resulting ester is boiled for /2 hour with 50 ml. of which 1s present on the 3-carbon atom of which bemg hydrobromic acid and the resulting solution evaporated then acylatfd Wlth 'Q PY P acld'hahde followed 5 to dryness in vacuo. On recrystallization from alcohol by deacylation of .the O-acyl group: CH2 -OHCHl GEL-CH2 CHr-----CH-CH2 In order that the invention may be well understood the compound described in Example 1 is obtained, M. P.

the following examples are given only as illustration: 221 C.

Exam 1e 1 We claim:

p 1. As new compounds, compounds of the general 28.9 g. of dl-tropic acid ester of the tropine is dissolved formula GHa-- cH--oHi @O l is? C a------CHCHz in 300 ml. of luke-warm acetone and to the solution. wherein X is halogen.

are added 25 g. of 4-diphenyl-methyl-bromide, dissolved 2. The new compound set forth in claim 1 in which X in 75 ml. of acetone. The solution is kept for 1 hour at is bromine. room temperature, thereafter during 6 hours at 40-60" C. 3. A process for the preparation of the compounds The separated quaternary salt is filtered 01f, washed with of the formula 0H (in-0H.

v is...

acetone and dried at gentle heat. Yield, 35-39 g. After wherein X is halogen, in which the tropic acid ester of the recystallizing in ethyl alcohol one obtains a snow-white tropine is reacted with a 4-diphenyl-methyl-halide.

microcrystalline powder which at a heating velocity of 4. A process as claimed in claim 3, inwhich the reac- 100'/7.5 minutes melts at 220-222" C. with decomposit-ion is carried out in the presence of an inert solvent. tion. 5-. A process as claimed in claim 3 in which the 4-di- Example 2 phenyl-methyl-halide is 4-diphenyl-methyl-bromide. 14.1 g. of trans-tropanol are dissolved in 150 ml. of 6. A process for the preparation of compounds of the acetone and the solution mixed with 24.7 g. of 4-diphenyl formula Hr------- OH-CH1 on]? CEO-CO-OH-O w s I CHrOH oH.---------oH-on,

methyl-bromide dissolved in a little acetone. The soluin which the quaternary compound formed from tropanol tion is kept for some hours at about'SO C. and therefater and a 4-diphenyl-methyl-halide is reacted with an O-acylthe separated 4-diphenyl-methyl-trans-tropinium-bromide tropic acid-halide and the O-acyl group is then deacy-- is isolated in the usual manner. Yield about 90%. After lated from the reaction product.

recrystallising in ethyl alcohol the compound melts at 7. A process as claimed in claim 6, in which the about 230 with decompositionquaternary compound formed from tropanol and 4- 19.4 g. of the quarternary aminoalcohol obtained in diphenyl-methyl-tropinium-bromide is reacted with O- the above manner is mixed with 13.5 g. of O-acetyl-dlacyl-tropic acid bromide and the O-acyl group is then tropic acid bromide, in a vessel provided with a tube condeacylated from the reaction product.

taining calcium chloride, and the mixture is warmed in u an oilbath at l20-l30 C. until no more delevopment 70 I No references cited. 

1. AS NEW COMPOUNDS, COMPOUNDS OF THE GENERAL FORMULA 